No More Antixoxidants

This fascinating blog post by Josh Mittledorf points out that antioxidants, once believed to reduce aging by reducing oxidative damage, have turned out to have the opposite effect. By reducing a hormetic effect, they make things worse. I’m a friend of Bruce Ames, one of main proponents of the free radical theory of aging. I’ve heard him talk about it a dozen times. The turning point — the beginning of the realization that this might be wrong — was this 1994 study, which found that beta-carotene, a potent antioxidant, increased mortality. Bruce did not have a good explanation for the counter-theoretical result. However, Mittledorf doesn’t mention an important fact which doesn’t fit his picture. Selenium, a potent antioxidant, also powerfully reduces cancer. Don’t stop taking selenium.

I also like this theoretical paper by Mittledorf about why aging evolved (turning off certain genes reduces aging) and how its evolution — not easily explained by conventional evolutionary ideas — is part of a range of phenomena that the conventional ideas cannot explain. One reason, maybe the main reason, that aging is adaptive is very Jane Jacobsian: it makes the community more flexible. Less likely to repeat old ways of doing things.

13 Replies to “No More Antixoxidants”

I think there is more to this than just anti-oxidants = bad. That trial with beta carotene is confounded by the addition of synthetic alpha tocopherol. We know from other trials that synthetic fat soluble vitamins are bad news.

I personally take a low dose natural vitamin e supplement that includes mixed tocotrienols (which balance tocopherols) and ultrathione, a highly absorbable version of glutathione, the so-called ‘master anti-oxident’, I’ve had great results with both. Namely glowing skin and good stable mood.

I think hormetic stress is important, in fact that is how polyphenols found in vegetables and exercise benefits are now thought to come about, but that doesn’t mean the chronic oxidative stress we experience in modern life is not to be avoided and mitigated where possible.

Seth: The trial was not confounded. Betacarotene and vitamin e were varied separately. There were four groups, on other words.

Three take-away lessons that I get from all these changing and contradictory studies — and all the drug recalls — are very simple:

1. All the smug self-proclaimed experts are not as smart as they think they are.

2. We should be very careful about interfering with biological processes that have been selected for over millions of years of Darwinian evolution.

3. We should be especially careful about all the highly profitable new drugs, devices and surgeries. As for me, I’m perfectly happy to let other people be the guinea pigs taking — and dying from — all the addictive painkillers, antidepressants, prpton pump inhibitors, and other magic BigPharma potions.

Does the 1994 study and the vast majority of all vitamin studies show that supplementing with isolated chemically derived vitamins is neutral at best and negative at worst? One wonders if the 1994 study results would have been different had one group eaten carrots and the other not eaten carrots.

Seth: If you include animal (usually rat or mouse) experiments, I believe the answer is no, they don’t show that. The vast majority of vitamin experiments with isolated chemicals (lab chow with chemical X vs lab chow without chemical X) have produced positive results. That’s where the concept of vitamin came from. In these studies the animals were made sure to have a deficiency in the vitamin. Whereas human studies often fail to make sure there is a deficiency.

If I remember correctly, the idea that antioxidants would slow aging was very abstract. The takeaway might be that biology is sufficiently complex that experiments and knowledge of specific mechanisms are essential.

“The vast majority of vitamin experiments with isolated chemicals (lab chow with chemical X vs lab chow without chemical X) have produced positive results. That’s where the concept of vitamin came from. In these studies the animals were made sure to have a deficiency in the vitamin. Whereas human studies often fail to make sure there is a deficiency. ”

Good point, Seth. The argument I’ve heard for why the CARET study possibly failed, from the Eades, is that the immune system system uses free radicals and that supplying one specific anti-oxidant could actually compromise that process. Hence the need to supply a natural smorgasbord of anti-oxidants and their raw materials to let the body select what it wants to use. But I’ve heard the same argument used for vitamins, whereas it’s clear that extracted or isolated vitamins will always cure their associated deficiency diseases.

There are certain diseases – hepatitis, pancreatitis, and various types of poisoning are good examples – where antioxidants – pretty much generically and indiscriminately – can save your life.
Otherwise, beneficial antioxidants fall into groups:
1) antioxidants that are also pro-oxidants, so don’t suppress important ROS signalling. Co-enzyme Q10, carnitine, ascorbate.
2) components of antioxidant enzymes; selenium, zinc, copper, manganese, iron and NAC/cysteine/glutathione.
3) plant polyphenols that stimulate the formation of enzymes as in 2) and may not even be antioxidant in vitro except as chelators of free iron.

Fat soluble antioxidants are valuable in some contexts – mixed carotenoids or astaxanthin protect against UVA in summer, tocopherols protect against the oxidation of the PUFAs that naturally contain them.

Apart from grossly purified or otherwise unnatural forms of some fat-soluble antioxidants – as in CARET – where the vitamins were, to be fair, combined with smoking, which no-one thinks is a good idea – it is hard to discover much harm in the clinical literature. There’s not a lot of benefit either, but I imagine that a varied approach tailored to the needs of each patient – which has NEVER been the kind of medicine subject to published analysis, yet is the only responsible way to practice – can produce marked benefit – this was certainly my experience.

Should a healthy person supplement antioxidants? Maybe not.
Should an unhealthy person try those antioxidants that are most likely to be of benefit for their symptoms?
Why not? If you can relieve pain or reverse degenerative disease with supplements, and you do notice improvement, and you have avoid the added risk of using drugs, maybe you’ve achieved something.
Many effective antioxidants, such as polyphenols, curcumin, astaxanthin, acetyl-carnitine, lipoic acid have anti-inflammatory effects or metabolic effects that might overshadow their ability to quench free radicals. Free radical signalling is significant in the cytosol, between mitochondria and nucleus, and promotes (via FOXO1) elevations in glutathione and antioxidant enzymes – it is self regulating. When this self-regulation breaks down (because minerals or protein is deficient, toxins are involved, or hyperglycaemic conditions are causing maladaptive signalling, i.e. oxidative stress) then supplementary antioxidants are cytoprotective.

I once read a book by the professor who called himself the “Father of Antioxidants” and he wrote about the anti- and pro-oxidant effects. He boosted the notion of 5 antioxidants that work in concert: one would produce oxidants that another would gobble onto, and so on in a ring. C, E, selenium I think were 3 of the 5.

According to this notion, doing a study of one antioxidant alone would lead to contradictory results, depending on whether the other antioxidants were being consumed in diet in enough quantities.

The synergistic notion makes sense in evolutionary biology terms, since traditionally we consumed all vitamins in our diet.

You could explain the CARET study without mentioning ROS signalling. High vitamin A intakes disordering cell growth signalling in people already deficient in vitamin D; high carotene intakes in oxidative stress conditions forming toxic apocarotenoids, which further disrupt vitamin A signalling. The net effect could also be immunosuppressive.
I’m not saying this does in fact explain it, but there are other pathways involved other than the antioxidant effect.

“A common explanation of the effect is that when retinoic acid is liganded to RAR-beta (Retinoic Acid Receptor beta), the complex binds AP1 (Activator Protein 1).

AP1 is a transcription factor that binds to DNA and in downstream events promote cell proliferation. Therefore, in the presence of retinoic acid, the retinoic acid:RAR-beta complex binds to AP1 and inhibit AP-1 from binding to DNA. In that case, AP1 is no longer expressed, and cell proliferation does not occur.

Cigarette smoke increases the asymmetric cleavage of beta-carotene, decreasing the level of retinoic acid significantly. This can lead to a higher level of cell proliferation in smokers, and consequently, a higher probability of lung cancer.

Another β-carotene breakdown product suspected of causing cancer is trans-beta-apo-8′-carotenal (common apocarotenal), which has been found in one study to be mutagenic and genotoxic in cell cultures which do not respond to β-carotene itself.”